The present invention relates to sulfonamide derivatives having tubulin polymerization inhibitory activity, and tubulin polymerization inhibitory agents, anticancer agents, and agents useful as preventives or remedies for rheumatism such as inflammatory rheumatism containing these derivatives as the active ingredients.
Rheumatism is a refractory disease. Rheumatoid arthritis (RA), for example, has the basal lesion in proliferation of synovial cells accompanied with abnormalities in immune system caused by various factors. RA often causes progressive dysfunctions in articulation. To prevent from dysfunctions by RA, which is considered to be an auto immune disease, agents correcting immune abnormalities are used in combination to general antiphlogistics under the expectation of altering natural couse of RA.
For remedy of arthritis, steroidal agents such as adrenocortical hormones including cortisone, non-steroidal anti-inflammatory agents such as aspirin, piroxicam and indometacin, antirheumatic agents such as gold preparations including aurothiomalate, D-penicillamines, and immunosuppressive agents such as cyclophosphamide and azathioprine have been used.
Recent Japanese reports suggest that an intermittent administration in low dose of methotrexate(MTX) result in high efficiency and rapid response. However, it has many side effects including interstitial pneumonia, stomatitis, gastrointestinal symptons such as nausea and vomition, fibrous liver, and marrow suppression. Furthermore, a long term of the therapeutic administrations may cause high infectiousness and complicated malignancy. There has been found no desirable drug which is really effective and has little side effects with respect to this disease.
Although many compounds having tubulin polymerization inhibitory activity have been reported, nothing but colchicine(an arthrifuge) and vincristine(an antineoplastic) (Cancer Reseach, vol.20, p1023, 1960) among them are applicable for therapeutic agents. Rheumacon, the glycoside extracted from the natural material having antirheumatic effect is reported to show tubulin polymerization inhibitory effect(British Journal of rheumatology, Vol.32, p804, 1993), but it has the unknown chemical structural formula and many side effects such as moon face, suffusion, and gastrointestinal disorder are reported.
The JP Laid-Open No.39256/1993 discloses that the other sulfonamides than those of the present invention are useful antineoplastics. N-[2-((4-hydroxyphenyil) amino)-3-pyridinyl]-4-methoxybenzenesulfonamide described in the publication is reported to show tubulin polymerization inhibitory effect (Cancer Research, Vol.54, p1702, 1994).
However, the above agent has the severe side effects which make impossible its continuous administrations, the poor sustained therapeutic effects, or no effects for some patients. The clinical therapy demands low toxic agents which can protect and remedy patients from RA through new mechanism.
For solving the above problem, the present inventors made diligent studies to achieve low toxic anticancer agents and agents useful as preventives or remedies for rheumatism such as inflammatory rheumatism. As the result, it has been found that the novel sulfonamides derivatives having tubulin polymerization inhibitory activity as described below are lowly toxic, effective as anticancer agents, and useful as preventives or remedies for rheumatism such as inflammatory rheumatism. This finding has led to the completion of the present invention.
The compounds of the present invention as shown by the general formula(1) are novel(except the case that A is triazol in the formula(1) ) and their medical uses are unknown together with the case that A is triazol.
The present invention relates to the foliowing(i) to (x i).
(i) Sulfonamide derivatives represented by the general formula(1) 
[wherein R1, R2 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, a cyano group, a C1 to C8 acyl group, an optionally substituted phenoxy group, or an optionally substituted amino group;
R3, R4 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, a hydroxy group, a group as shown by the general formula(2) described below:
xe2x80x94(CH2)nxe2x80x94COxe2x80x94R7xe2x80x83xe2x80x83(2)
(wherein R7 represents a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, or an optionally substituted amino group, and n means an integer of 1-5), a group as shown by the general formula(3) described below:
xe2x80x94(CH2)nxe2x80x94Bxe2x80x83xe2x80x83(3)
(wherein B represents an imidazolyl group, a triazolyl group, a tetrazolyl group, or an optionally substituted amino group, and n means any integer of 1-5), a group as shown by the general formula(4) described below: 
(wherein R8 represents a lower alkyl group, a C1 to C5 alkyl group substituted by 1 or 2 hydroxy group(s), a C1 to C5 alkyl group substituted by a C1 to C5 alkoxycarbonyl group, a C1 to C5 acyl group, or a pyridyl group; R9 represents a lower alkyl group or a hydroxy group; a and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(5) described below: 
(wherein R9 represents a lower alkyl group or a hydroxy group; b and n means any integer of 0-3 and 0-6 respectively), a group as shown by the general formula(6) described below: 
(wherein R9 represents a lower alkyl group or a hydroxy group; c and n means any integer of 0-3 and 0-6 respectively; Q represents an oxygen atom, a sulfur atom, or a group as shown by the general formula(7) described below: 
(wherein d means 1 or 2) ), a group as shown by the general formula(8) described below:
xe2x80x94(CH2)nxe2x80x94N R10 R11xe2x80x83xe2x80x83(8)
(wherein R10 , R11 may be the same or different and each independently represents a hydrogen atom, a lower alkyl group or an optionally substituted amino lower alkyl group; n means any integer of 0-6), a group as shown by the general formula(9) described below:
xe2x80x94(CH2)nxe2x80x94S(O)exe2x80x94R12xe2x80x83xe2x80x83(9)
(wherein R12 represents a hydrogen atom, a lower alkyl group or an aryl group, an aralkyl group or an optionally substituted amino group; e and n means any integer of 0-3 and 0-6 respectively) or a group as shown by the general formula(10) described below:
xe2x80x94(CH2)nxe2x80x94OR13xe2x80x83xe2x80x83(10)
(wherein R13 represents a hydrogen atom, a lower alkyl group or an acyl group, a phosphate group or an optionally substituted aminoalkyl group; and n means any integer of 1-6),
R5, R6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, an acyl group, or an optionally substituted amino group; A represents any group of (1) an optionally substituted 5-membered heterocyclic group (except triazol) whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, (2) an optionally substituted alicyclic group, and (3) an alicyclic group whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom], and the pharmaceutically acceptable salts thereof.
(ii) Sulfonamide derivatives as defined in (i), wherein R1 is a lower alkoxy group, and R2, R3, R4, R5, and R6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, or an optionally substituted amino group, and the pharmaceutically acceptable salts thereof.
(iii) Sulfonamide derivatives as defined in (i), wherein R1 is a lower alkoxy group, and R2 R3, R4 R5 and R6 may be the same or different and each independently represents a hydrogen atom, a halogen atom, a lower alkyl group, or an optionally substituted amino group, and A represents an optionally substituted 5-membered heterocyclic group (except triazol) whose ring members include at least 1 nitrogen atom and may include any atom(s) selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, and the pharmaceutically acceptable salts thereof.
(iv) Sulfonamide derivatives as defined in any one of (i)-(iii), wherein A represents an optionally substituted isoxazol group, and the pharmaceutically acceptable salts thereof.
(v) Sulfonamide derivatives as defined in (iv), wherein A represents a 4-isoxazol group which has at least one lower alkyl group at the 3- and 5- position, and the pharmaceutically acceptable salts thereof.
(vi) Sulfonamide derivatives as defined in (i), wherein R1 is a lower alkoxy group which is located at the para-position, and R2 to R6 are hydrogen atoms, and the pharmaceutically acceptable salts thereof.
(vii) A pharmaceutical composition containing as an active ingredient the sulfonamide derivatives (including the case that A is triazolyl group in the general formula(1)) as defined in any one of (i)-(vi), or the pharmaceutically acceptable salts thereof.
(viii) A tubulin polymerization inhibitory agent containing as an active ingredient the sulfonamide derivatives (including case that A is triazolyl group in the general formula(1)) as defined in any one of (i)-(vi), or the pharmaceutically acceptable salts thereof.
(ix) An anticancer agent containing as an active ingredient the sulfonamide derivatives (including the case that A is triazolyl group in the general formula(1)) as defined in any one of (i)-(vi), or the pharmaceutically acceptable salts thereof.
(x) A drug as a preventive or a remedy for rheumatism containing as an active ingredient the sulfonamide derivatives (including the case that A is triazolyl group in the general formula(1)) as defined in any one of (i)-(vi), or the pharmaceutically acceptable salts thereof.
(xi) A drug as a preventive or a remedy for rheumatism as defined in (x), wherein rheumatism is inflammatory rheumatism.
The present invention will be more particularly described below.
Lower alkyl groups of the present invention are C1-C6 straight chain or branched alkyl groups including methyl group, ethyl group, n-propyl group, isopropyl group, nbutyl group, sec-butyl group, tert-butyl group, n-pentyl group, amyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-metylpropyl group. These groups may have Additional substituents as long as they provide no special interference. C1-C4 alkyl groups are preferable, C-C3 alkyl groups are more preferable, and methyl group and ethyl group are the most preferable.
Lower alkoxy groups of the present invention are C1-C6 straight chain or branched alkoxy groups including methoxy group, ethoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group. These groups may have additional substituents as long as they provide no special interference. C1-C4 alkoxy groups are preferable, C1-C3 alkoxy groups are more preferable, and methoxy group and ethoxy group are the most preferable.
Halogen atoms of the present invention includes fluorine atom, chlorine atom, and bromine atom.
Substituents connected to nitrogen atoms, for example,to those found in amino groups include lower alkyl groups, and C1-C8 acyl groups (including C1-C8 alkoxycarbonyl group). These groups may have additional substituents as long as they provide no special interference.
Optionally substituted amino groups include unsubstituted amino group, lower acylamino groups (for example, amino groups substituted with C1-C4 acyl groups such as formylamino group, propionylamino group), optionally substituted alkoxycarbonylamino groups (for example, benzyloxycarbonylamino group), and mono- or di-lower alkylamino groups (for example, N,N-dimethyl-amino group, N,N-diethylamino group, N,N-dipropylamino group, N,N-diisopropylamino group, N,N-di-n-butylamino group). optionally substituted aminoalkyl groups include unsubstituted aminoalkyl groups and mono- or di-lower alkyl substituted aminoalkyl groups (C1-C10)such as N,N-diethylaminoethyl group, N,N-dimethylaminomethyl group, N,N-dimethylaminoethyl group, and N,N-dimethylaminoethyl group.
Alicyclic hydrocarbon groups (groups represented by removing onehydrogenatomfromthecorrespondingalicyclic hydrocarbon), which are included in A of the present invention, include 3 to 10-membered alicyclic hydrocarbon groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group. 5 to 7-membered alicyclic hydrocarbon groups such as cyclohexyl group, cycloheptyl, and cycloheptyl group are preferable.
5-membered Heterocyclic hydrocarbon groups having at least one nitrogen atom, which are included in A of the present invention, mean groups represented by removing one hydrogen atom from any carbon atom of the corresponding 5-membered heterocyclic hydrocarbon rings, which have at least-two unsaturated bond and contain preferably at least two heteroatoms. They include pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, and tetrazolyl group. Oxazolyl group, isoxazolyl group, and isothiazolyl group are preferable, and isoxazolyl group is more preferable.
Alicyclic hydrocarbon groups having at least one nitrogen atom in the rings, which are included in A of the present invention, mean groups represented by removing one hydrogen atom from any carbon atom of the corresponding alicyclic hydrocarbon rings, which may have one unsaturated bond and contain preferably at least two heteroatoms. The heteroatom may be selected from the group containing of nitrogen atom, oxygen atom, and sulfur atom. They include 3 to 10-membered alicyclic hydrocarbon groups having at least one nitrogen atom in the rings such as aziridinyl group, azethidinyl group, pyrrolidinyl group, piperidinyl group, oxazolinyl group, isoxazolidinyl group, thiazolidinyl group, imidazolidinyl group, and pyrrazolidinyl group. Thiazolidinyl group is preferable.
Substituents of the present invention bonding to any carbon atom of alkyl groups or cyclic (optionally containing hetero atom(s)) hydrocarbon groups include lower alkyl groups, lower alkoxy groups, optionally substituted amino groups, halogen atoms, nitro groups, hydroxy group, carboxyl groups, acyl groups (including optionally phenyl-substituted alkoxycarbonyl), cyano group, and phenyl group. These groups may have additional substituents as long as they provide no special interference. Lower alkyl groups are preferable for substituents of the groups A.
Acyl groups of the present invention include C1-C8 acyl groups such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, optionally substituted benzoyl group, and optionally substituted benzyloxycarbonyl group. Substituents bonding to the benzoyl group or the benzyloxycarbonyl group include the substituents bonding to the carbon atom as described above.
Substituents bonding to optionally substituted phenoxy group of the present invention include the substituents bonding to the carbon atom as described above.
Optionally substituted amino lower alkyl groups of the present invention include C1-C3 alkylamino-substituted C1-C3 alkyl groups, alicyclic alkylamino-substituted C1-C3 alkyl groups, and aromatic amino-substituted C1-C3 alkyl groups where alicyclic alkyl groups include C3-C6 groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group, and aromatic groups include C1-C10 groups such as phenyl group and naphthyl group.
Aralkyl groups of the present invention include C7-C11 groups such as benzyl group.
xe2x80x94(CH2)n-groups of the present invention include methylene group, dimethylene group, trimethylene group, and tetramethylene group.
The groups as shown by the general formula (2) include carboxymetyl group, methoxycarbonylmethyl group.
The groups as shown by the general formula (3) include imidazolylmethyl group, triazolylmethyl group, tetrazolylmethyl group, aminoethyl group.
The groups as shown by the general formula(4) include 4-methyl-3-methylpiperadinylmethyl group.
The groups as shown by the general formula(5) include 4-methyl piperidinyl methyl group.
The groups as shown by the general formula(6) include 1-morphorino methyl group.
The groups as shown by the general foraula(8) include dimethylaminoethyl group.
The groups as shown by the general formula(9) include sulfonylmethyl group.
The groups as shown by the general formula (10) include hydroxy methyl group and methoxyethyl group.
In the present invention, preferable groups in R1 are lower alkoxy groups located at the para position, and each preferable group in R2, R3, R4, R5, and R6 is hydrogen atom. Preferable groups in A include thiazolidinyl group, C3-C6 alicyclic groups, pyrrolyl group, oxazolyl group, isoxazolyl group. Particularly preferable in A is 4-isoxazolyl group, which is more preferable if it has at least one substituent at the 3- and 5-position, and is the most preferable if it has methyl group or ethyl group both at the 3- and 5- positions. Preferable 4-isoxazolyl groups are, For example, 3-methyl-4-isoxazolyl group, 3,5-dimethyl-4-isoxazolyl group, 5-ethyl-3-methyl-4-isoxazolyl group, 3-ethyl-5-methyl-4-isoxazolyl group, 3,5-diethyl-4-isoxazolyl group. Combination of these preferable groups leads to the most preferable compound among all the sulfonamide derivatives as represented by the general formula(1).
Sulfonamide derivatives of the present invention may react with acids to form their salts, which are also covered by the present invention. Their salts include the salts of inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid and the salts of organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid.
The present invention covers all the hydrates and all the optical isomers, if any.
The compounds represented by the general formula(1) include:
(1)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide
(2)N-[2-(4-methoxybenzenesulfonamide)phenyl]-1,3-dimethyl-4-(1H-pyrazole)carboxamide
(3)N-[2-(4-methoxybenzenesulfonamide)phenyl]-2-methyl-4-thiazole carboxamide
(4)N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-methyl-4-isothiazole carboxamide
(5)N-[2-(4-methoxybenzenesulfonamide)phenyl]-2,5-dimethyl-4-oxazole carboxamide
(6)N-[2-(4-methoxybenzenesulfonamide)phenyl]-1-methyl-1H-imidazole-4-carboxamide
(7)N-[2-(toluenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide
(8)N-[2-(benzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide
(9)N-[2-(4-fluorobenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide
(10)N-[2-(4-nitrobenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide
(11)N-[2-(3,4-dimethoxybenzenesulfonamide)phenyl]-5-methyl-4-isoxazole carboxamide
(12)N-[2-(4-methoxybenzenesulfonamide)phenyl]-(L)-prolinamide
(13)N-[2-(4-methoxybenzenesulfonamide)phenyl]-3,5-dimethyl-4-isoxazole carboxamide
(14)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-ethyl-4-isoxazole carboxamide
(15)(xc2x1)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-4-thiazolidine carboxamide
(16)(xc2x1)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-(N-methylpiperidine)carboxamide
(17)N-[2-(4-methoxybenzenesulfonamide)phenyl]-(D)-prolinamide (18)N-[2-(4-methoxybenzenesulfonamide)phenyl]-4-piperidine carboxamide
(19)(xc2x1)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-piperidine carboxamide
(20)(xc2x1)-N-[2-(4-methoxybenzenesulfonamide)phenyl]-2-piperidine carboxamide
(21)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-4-oxazole carboxamide
(22)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclohexyl carboxamide
(23)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclopropyl carboxamide
(24)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclobutyl carboxamide
(25)N-[2-(4-methoxybenzenesulfonamide)phenyl]-cyclopentyl carboxamide
(26)N-[2-(4-methoxybenzenesulfonamide)phenyl]-N-methyl-2-pyrrole carboxamide
(27)N-[2-(4-methoxybenzenesulfonamide)phenyl]-3-ethyl-5-methyl-4-isoxazole carboxamide
(28)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-ethyl-3-methyl-4-isoxazole carboxamide
(29)N-[2-(4-methoxybenzenesulfonamide)phenyl)-3,5-diethyl -4-isoxazole carboxamide
(30)N-C2-(4-methoxybenzenesulfonamide)phenyl]-5-isopropyl-3-methyl-4-isoxazole carboxamide
(31)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-3-phenyl-4-isoxazole carboxamide
(32)N-[2-(4-methoxybenzenesulfonamide)phenyl]-5-methyl-3-phenyl-4-isoxazole carboxamide
The compounds of the present invention, which are novel and have not yet published in any documents, can be produced, for example, by the following reaction: 
The novel sulfonamide derivatives represented by the general formula(1) can be produced by reacting compounds as shown by general formula(11) described below, 
(wherein R1, R2, R3, R4, R5, and R6 have the same meaning as mentioned before) with carboxylic acids or their reactive derivatives (whose functional groups may be protected if they are not associated with the reaction)as shown by general formula (12) described below,
Axe2x80x94Zxe2x80x83xe2x80x83(12)
(A has the same meaning as mentioned before, and Z represents carboxyl groups or the reactive groups derived therefrom).
The reaction is preferably carried out under the presence of a base.
Most of the compounds represented by the general formula(11) are known to the public, and the others can be prepared by the method JP Laid-Open No.39256/1993 has disclosed, or its modifications.
Any reactive derivatives that are generally used to form carboxamide bonds can be applied for reactive derivatives of carboxylic acids represented by the general formula(12). They include acid halides, active amides, and active esters. They may be prepared prior to the reaction or planned to form within the reaction system.
The acid halides, which include acid chloride and acid bromide, can be obtained generally by reacting carboxylic acids with thionyl halogenides.
For the active amides, there can be used acid amides of, for example, imidazole, pyrazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole, and benzothiazole.
For the active esters, there can be used acid esters which include methyl esters, methoxymethyl esters, cyanomethyl esters, propagyl esters, 4-nitrophenyl esters, 2,4-dinitrophenyl esters, and esters of, for example, 1-hydroxybenzotriazole.
The carboxylic acids represented by the general formusa(12) may be reacted with the amines represented by the general formula(11) under the presence of condensation agents such as N,Nxe2x80x2-dicyclohexylcarbodiimide(DCC)and N-cyclohexyl-N-morpholino etylcarbodiimide. These reactions are preferably carried out under the presence of bases such as organic tertiary amines(for example, triethylamine, N,N-dimethylaniline, and pyridine).
The reaction solvents, which are desirable to use if they can dissolve the reaction-associated materials and have no reaction with them, include pyridine, tetrahydrofurane, dioxane, benzene, ether, methylene chloride, dimethylformamide, toluene, and the mixture solvents consisting of two or more solvents selected therefrom. But any reaction solvents can be used with no special limitation regardless of the above mentioned examples.
The reaction can be generally carried out at ambient temperature. Cooling or heating may be applied for the reaction if necessary. The reaction time is generally 5 min-20 hrs, and may be determined adequately depending upon materials and reaction temperature.
Deprotection such as acid treatment converts the reaction products, whose amino groups are protected, to the compounds represented by the general formula(1) which have the free amino groups.
The representative compounds as shown by the general formula(12) which are raw materials for syntheses include:
N-(2-aminophenyl)-4-methoxybenzenesulfonamide
N-(2-aminophenyl)-4-ethoxybenzenesulfonamide
N-(2-aminophenyl)-4-propoxybenzenesulfonamide
N-(2-aminophenyl)-3,4-dimethoxybenzenesulfonamide.
N-(2-aminophenyl)-4-toluenesulfonamide
N-(2-aminophenyl)-4-fluorobenzenesulfonamide
N-(2-aminophenyl)-4-nitrobenzenesulfonamide
The representative compounds as shown by the general formula(12) which are raw materials for syntheses include:
5-methylisoxazole-4-carboxylic acid
5-ethylisoxazole-4-carboxylic acid
3-ethyl-5-methylisoxazole-4-carboxylic acid
5-ethyl-3-methylisoxazole-4-carboxylic acid
3,5-diethylisoxazole-4-carboxylic acid
3,5-dimethylisoxazole-4-carboxylic acid
1,3-dimethyl-1H-pyrazole-4-carboxylic acid
2-methylthiazole-4-carboxylic acid
2,5-dimethyloxazole-4-carboxylic acid
N-methyl-1H-imidazole-4-carboxylic acid
N-(t-butoxycarbonyl)-L-proline
N-(t-butoxycarbonyl)-D-proline
N-(t-butoxycarbonyl)thiazolidine-4-carboxylic acid
N-methylpiperidine-3-carboxylic acid
N-(t-butoxycarbonyl)piperidine-4-carboxylic acid
N-(t-butoxycarbonyl)piperidine-3-carboxylic acid
N-(t-butoxycarbonyl )piperidine-2-carboxylic acid
cyclopropane carboxylic acid
cyclobutane carboxylic acid
cyclopentane carboxylic acid
cyclohexane carboxylic acid
1-metyl-2-pyrrole carboxylic acid
The sulfonamide derivatives represented by the general formula(1) or the pharmaceutically acceptable salts thereof may be administrated orally or parenterally(systemic or local effect)for medical use either alone or in various preparation forms such as pulver, granule, tablet, and injection manufactured by mixing with pharmaceutically acceptable additives such as vehicle, excipient, diluent, and solubilizer. Preparations should contain 0.1-100% by weight of the compounds of the present invention or the pharmaceutically acceptable salts thereof depending on the preparation forms. The doses should be determined depending on administration routes, patients"" ages, and disease symptoms to protect or cure from. The dose, for example, by oral administration for an adult is 0.1 mg-2,000 mg/day, and is preferably 1 mg-1,000 mg/day in one or more times per day.
The sulfonamide derivatives represented by the general formula(1) and the pharmaceutically acceptable salts thereof have tubulin polymerization inhibitory activity, and are useful as anticancer agents and preventives or remedies for rheumatism. Rheumatism herein includes, for example, inflammatory rheumatism such as rheumatoid artiritis and osteoarthritis etc.